Tumefactive multiple sclerosis and hepatitis C virus 2a/2C infection: Dual benefit of long-term interferon beta-1a therapy?

Hepatitis C virus (HCV) infection has been implicated in triggering acute disseminated encephalomyelitis but not tumefactive multiple sclerosis. We report the case of a 17-year-old female who presented with a 5-day history of left hemiparesis and hemisensory loss followed by a right third nerve palsy. Tumefactive multiple sclerosis was diagnosed based on the absence of encephalopathic signs, the presence of tumefactive brain lesions, the exclusion of neoplastic and infectious causes of the lesions by biopsy, and the occurrence of relapse after a period of remission. The patient was at risk for HCV infection due to parenteral drug abuse and multiple sexual partners. Serial HCV antibody tests and RNA polymerase chain reaction assays revealed acute HCV infection and genotyping showed HCV genotype 2a/2c. She was treated with high-dose methylprednisolone and discharged with only mild left hand weakness. Interferon beta-1a 30mcg was administered intramuscularly once a week. Remission from HCV infection was achieved in three years without standard anti-HCV therapy. This case suggests that CNS myelin is a potential target of the immune response to HCV 2a/2c infection, the HCV 2a/2c virus may be involved in triggering autoimmune tumefactive brain lesions, and interferon beta-1a is effective against HCV 2a/2c infection. We recommend serial HCV antibody testing and HCV RNA PCR assay, preferably with HCV genotyping, in all patients with acute inflammatory demyelinating diseases of the CNS.

Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells.

Although crosstalk between cell-surface and nuclear receptor signaling pathways has been implicated in the development and progression of endocrine-regulated cancers, evidence of direct coupling of these signaling pathways has remained elusive. Here we show that estrogen promotes an association between extranuclear estrogen receptor alpha (ER) and the epidermal growth factor receptor (EGFR) family member ERBB4. Ectopically expressed as well as endogenous ERBB4 interacts with and potentiates ER transactivation, indicating that the ERBB4/ER interaction is functional. Estrogen induces nuclear translocation of the proteolytic processed ERBB4 intracellular domain (4ICD) and nuclear translocation of 4ICD requires functional ligand-bound ER. The nuclear ER/4ICD complex is selectively recruited to estrogen-inducible gene promoters such as progesterone receptor (PgR) and stromal cell-derived factor 1 (SDF-1) but not to trefoil factor 1 precursor (pS2). Consistent with 4ICD-selective promoter binding, suppression of ERBB4 expression by interfering RNA shows that 4ICD coactivates ER transcription at the PgR and SDF-1 but not the pS2 promoter. Significantly, ERBB4 itself is an estrogen-inducible gene and the ERBB4 promoter harbors a consensus estrogen response element (ERE) half-site with overlapping activator protein-1 elements that bind ER and 4ICD in response to estrogen. Using a cell proliferation assay and a small interfering RNA approach, we show that ERBB4 expression is required for the growth-promoting action of estrogen in the T47D breast cancer cell line. Our results indicate that ERBB4 is a unique coregulator of ER, directly coupling extranuclear and nuclear estrogen actions in breast cancer. We propose that the contribution of an autocrine ERBB4/ER signaling pathway to tumor growth and therapeutic response should be considered when managing patients with ER-positive breast cancer.